The leading causes of blindness and low vision in the US include AMD, diabetic retinopathy and glaucoma. Current therapies offer few options to those suffering from late stages of these diseases. In order to explore possible therapies, it is important to use animal models with regenerative capabilities such as the chick embryo. Embryonic chicks regenerate their retina, following retinectomy, by reprogramming the remaining retinal pigmented epithelium (RPE) as long as an inducing factor is present. This reprogramming process allows the RPE to dedifferentiate, proliferate and form a neuro-epithelium that eventually differentiates generating retina. The process of dedifferentiation is ke to understanding how RPE reprogramming works. RPE reprogramming utilizes a two-step dedifferentiation process where injury (retinectomy) stimulates the RPE to become competent to respond to inducing factors. We have identified several inducing factors that are able to reprogram the RPE to neural retina, however, the role for these molecules in RPE reprogramming remains unknown. In this proposal we will dissect the mechanisms by which inducing factors such complement components C3a, C5a and inflammation associated molecules including IL-6 and antioxidant N-acetyl cysteine (NAC) reprogram the RPE. Specifically, we will explore if these factors/molecules exhibit interdependence, if they require common signaling pathways or if they regulate common target genes using similar or distinct epigenetic strategies. We will test the following hypothesis: Inducing factors direct RPE reprogramming and retina regeneration by initiating downstream signaling cascades such as MAPK, PI3K, Wnt and/or Jak/Stat pathways commonly activated by growth factor and G-coupled receptors. Through these pathways, the inducing factors epigenetically control common genes that regulate RPE reprogramming. The urgency for restoring vision lead the NEI to announce an audacious goal to restore vision through regeneration of neurons and neural connections in the eye and visual system. This study provides a model system where to test small molecules such as C3a, C5a, IL-6 and NAC to evaluate induction of retina regeneration and a platform where to dissect the cellular and molecular mechanisms involved in this process. This work will have a significant impact on the field of regenerative medicine since the information obtained can be extrapolated to the process of retina repair in mammals including humans, and specifically on the potential reprogramming of human RPE to generate new neurons.